Women are less susceptible than men to cardiovascular disease until they reach menopause, when cessation of ovarian hormone production is accompanied by an accelerated risk for atherosclerosis, coronary artery disease, and vascular dysfunction. Although several mechanisms by which estrogen may confer vascular protection have been proposed it remains unclear as to how estrogen exerts its beneficial effects on the vasculature. The main goal of this proposal is to examine the influence of estrogen on the regulation of sympathetic vasoconstriction in contracting skeletal muscle. To accomplish this goal complementary experiments will be performed in conscious humans and anesthetized rats. In pre and post-menopausal women changes in forearm muscle oxygenation and muscle sympathetic nerve activity will be measured during lower body negative pressure (LBNP) at rest and the responses will be compared to LBNP performed during rhythmic handgrip exercise. Studies will be performed when estrogen levels are high and again when estrogen concentrations are reduced to determine the impact of estrogen on sympathetically mediated vasoconstriction. In rats, the effect of lumbar sympathetic nerve stimulation on femoral blood flow and hind limb muscle oxygenation will be examined in resting and contracting hind limb of ovariectomized and sham rats. Further studies will examine influences of estrogen levels on neuronal nitric oxide synthase expression in skeletal muscle to determine its possible role in mediating a beneficial effect of estrogen on peripheral hemodynamics during muscle contraction.